Substrate Deacylation Mechanisms of Serine-.BETA.-lactamases

DOI IR Web Site Web Site 1 Citations 136 References
  • Hata Masayuki
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Fujii Yasuyuki
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Tanaka Yoshikazu
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Ishikawa Hidenori
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Ishii Miho
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Neya Saburo
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Tsuda Minoru
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University
  • Hoshino Tyuji
    Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University

Bibliographic Information

Other Title
  • Substrate Deacylation Mechanisms of Serine-β-lactamases
  • Substrate Deacylation Mechanisms of Serine ベータ lactamases

Search this article

Description

The substrate deacylation mechanisms of serine-β-lactamases (classes A, C and D) were investigated by theoretical calculations. The deacylation of class A proceeds via four elementary reactions. The rate-determining process is the tetrahedral intermediate (TI) formation and the activation energy is 24.6 kcal/mol at the DFT level. The deacylation does not proceed only by Glu166, which acts as a general base, but Lys73 also participates in the reaction. The C3-carboxyl group of the substrate reduces the barrier height at the TI formation (substrate-assisted catalysis). In the case of class C, the deacylation consists of two elementary processes. The activation energy of the TI formation has been estimated to be 30.5 kcal/mol. Tyr150Oη is stabilized in the deprotonated state in the acyl-enzyme complex and works as a general base. This situation can exist due to the interaction with two positively charged side chains of lysine (Lys67 and Lys315). The deacylation of class D also consists of two elementary reaction processes. The activation energy of the TI formation is ca. 30 kcal/mol. It is thought that the side chain of Lys70 is deprotonated and acts as a general base. When Lys70 is carbamylated, the activation energy is reduced to less than 20 kcal/mol. This suggests that the high hydrolysis activity of class D with carbamylated Lys70 is due to the reduction of activation energy for deacylation. From these results, it is concluded that the contribution of the lysine residue adjacent to the serine residue is indispensable for the enzymatic reactions by serine-β-lactamases.

Journal

Citations (1)*help

See more

References(136)*help

See more

Keywords

Details 詳細情報について

Report a problem

Back to top